Novel benzazepine derivatives

ABSTRACT

Novel 2,3,4,5-tetrahydro-1H-3-benzazepines having the formula ##STR1## wherein R 3  represents H, C 1-3  -alkyl or C 3-7  -cycloalkyl; R 4  represents hydrogen or R 4  together with R 10  represents a bridge which connects the positions to which R 4  and R 10  are linked, said bridge being --CH 2  --CH 2  --, --CH═CH--, --O--CH 2  -- or --S--CH 2  --; 
     R 7  represent hydroxy, lower alkoxy; 
     R 10 , R 11 , R 12  independently represent hydrogen or halogen or alkyl or alkoxy or trifluoromethyl, or R 10  together with R 4  represents a bridge as described in connection with the definition of R 4  ; or R 10  together with R 11  represents a bridge or R 11  together with R 12  represents a bridge, the bridge in both cases being chosen among --O--CH 2  --CH 2  --, --O--CH 2  --CH 2  --CH 2  --, --O-CH═CH--, --CH 2  -CH 2  -CH 2  --, --CH 2  -CH═CH-- or --CH 2  --CH 2  --CH 2  --CH 2  --; 
     R 13  represents hydrogen, halogen or lower alkyl. 
     The compounds are useful in preparations for treatment of disorders in the central nervous system.

This invention relates to novel 2,3,4,5-tetrahydro-1H-3-benzazepines andpharmaceutically acceptable acid addition salt thereof, to methods fortheir preparation, to pharmaceutical compositions containing them, andto their use in the treatment of certain disorders in the centralnervous system.

In the last decade, intensive pharmacological research concerningbenzazepines has taken place. The pharmacological properties ofbenzazepines depend to a large extent on the substituents. For example,substituted benzazepines exhibiting neuroleptic, antiaggressive,antiparkinson and certain vascular effects, are known.

In U.S. patent specification No. 3,393,192 (Schering) derivatives of5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine having, inter alia,hydroxy, lower alkoxy or halogen in the 7- and/or 8-position aredescribed.

In European patent applications publication Nos. 5,298 and 5,299(Scherico) the corresponding 7-hydroxy derivatives are described.

In European patent application publication No. 200,455 (NOVO)2,3,4,5-tetrahydro-1H-3-benzazepines having a heterocyclic or anortho-fused heterocyclic ringsystem in the 5-position are described.These compounds are claimed to have antipsychotic and antidepressiveeffects.

Furthermore, it has been reported in Eur.J.Pharmacol. 91 (1983) 153 etseq., that(R)-8-chloro-7-hydroxy-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine(designated SCH 23390) is a selective D1 dopamine antagonist (see alsoEuropean patent application publication No. 5,300 (Scherico)).

A common drawback which seriously limits the use of the above-mentionedbenzazepines is their low bioavailability after oral administration.

Thus, one object of the present invention is to provide compounds whichare dopamine antagonists.

A second object of the present invention is to provide compounds whichare useful as neuroleptics.

A third object of the present invention is to provide compounds whichcan be used for the treatment of various mental disorders, e.g.manic-depressive disorders.

A fourth object of the present invention is to provide substitutedbenzazepines which have a favourable bioavailability after oralingestion.

It has now been found that novel 2,3,4,5-tetrahydro-1H-3-benzazepines ofthe general formula I ##STR2## wherein R³ represents H, C₁₋₃ -alkyl orC₃₋₇ -cycloalkyl; R⁴ represents hydrogen or R⁴ together with R¹⁰represents a bridge which connects the positions to which R⁴ and R¹⁰ arelinked, said bridge being --CH₂ --CH₂ --, --CH═CH--, --O--CH₂ -- or--S--CH₂ --; R⁷ represents hydroxy or lower alkoxy; R¹⁰, R¹¹ and R¹²independently represents hydrogen, halogen, alkoxy, trifluoromethyl, oralkyl or R¹⁰ together with R⁴ represents a bridge as described inconnection with the definition of R⁴ ; or R¹⁰ together with R¹¹represents a bridge or R¹¹ together with R¹² represents a bridge, thebridge in both cases being chosen among --O--CH₂ --CH₂ --, --O--CH₂--CH₂ --CH₂ --, --O--CH═CH--, --CH₂ --CH₂ CH₂ --, --CH₂ --CH═CH-- or--CH₂ --CH₂ --CH₂ --; R¹³ represents hydrogen, halogen or lower alkyland pharmaceutically acceptable acid addition salts thereof, exhibituseful pharmacological properties, especially on the central nervoussystem, and that they have a surprisingly favourable bioavailabilityafter oral administration.

DETAILED DISCUSSION OF THE INVENTION

The prior art does not suggest that a particular pharmacologicaladvantage can be expected as a result of the specific substitutionpattern present in the structures of the benzazepines of this invention.

The compounds of formula I exhibit a strong antidopaminergic effect.Thus, they potently inhibit stereotyped gnawing behaviour in miceinduced by methylphenidate (testing performed as previously described inActa Pharmacol. Toxicol. 31 (1972) 488), and they also inhibitconditioned avoidance response and amphetamine cue in rats.

The benzazepine derivative SCH 23390 has been reported to exhibit a poorbioavailability after oral administration and a short duration of action(vide Life Sci. 34 (1984) 1529). The compounds of formula I exhibit afavourable bioavailability.

The compounds of formula I may be present as a mixture of opticalisomers which may be resolved into the individual pure isomers. Thisresolution may conveniently be accomplished by fractionalcrystallization, from appropriate solvents, of the salts of thecompounds of formula I with optically active acids. When the opticalisomers are resolved the desired pharmacological activity usuallypredominates in one of them. Therefore, this invention includes allisomers, whether resolved or mixtures thereof.

Throughout this specification, the term alkyl when used alone or in acombination like alkoxy represents a straight or branched chain with notmore than four carbon atoms, for example methyl, ethyl, propyl,isopropyl and tert- butyl. By the term alkoxy is preferably intendedmethoxy and ethoxy. Halogen is fluoro, chloro, bromo and iodo,preferably chloro and bromo.

According to the above definitions, the substituents designated R⁴, R¹⁰,R¹¹, and R¹² may be involved in the formation of bridges. Thus, when R⁴forms a bridge together with R¹⁰ a tetracyclic, ortho-fused ring systemis obtained except when R¹¹ at the same time forms a bridge togetherwith R¹² so that a pentacyclic system of ortho-fused ring results.

Particularly valuable embodiments of this invention are nontoxic,pharmaceutically acceptable acid addition salts of benzazepines offormula I. Such salts include those derived from inorganic and organicacids such as hydrochloride, hydrobromic, sulphuric, phosphoric,methane-sulphonic, acetic, lactic, maleic, phthalic and tartaric acids.They may be prepared by standard procedures, such as mixing a solutionof the base in acetone or in a lower alcohol with the stoichiometricalamount of the acid in a solvent, such as acetone or a lower alcohol, andevaporating the solvent to leave the desired salt as a residue.

In one group of preferred benzazepines of formula I, R³ is methyl.

In a second group of preferred benzazepines of formula I, R⁴ is hydrogenor R⁴ together with R¹⁰ is a bridge of the formula --O--CH₂ -- which isoriented so that the carbon atom is linked to the benzazepine nucleus orR⁴ together with R¹⁰ is a bridge of the formula --CH₂ --CH₂ --.

In a third group of preferred benzazepines of formula I, R⁷ is hydroxy.

In a fourth group of preferred benzazepines of formula I, R¹⁰ togetherwith R¹¹ is a bridge of the formula --O--CH₂ --CH₂ -- or --O--CH═CH--with the group comprising both possible orientations of the bridges.

In a fifth group of preferred benzazepines of formula I, R¹⁰ togetherwith R¹¹ is a bridge of the formula --O--CH₂ --CH₂ --CH₂ -- or --CH₂--CH₂ --CH₂ --CH₂ -- with the group comprising both possibleorientations of the oxygen containing bridge.

In a sixth group of preferred benzazepines of formula I, R¹⁰ togetherwith R¹¹ is a bridge of the formula --CH₂ --CH₂ --CH₂ -- or --CH₂--CH═CH-- with the group comprising both possible orientations of thedouble bond.

In a seventh group of preferred benzazepines of formula I, R¹¹ ishydrogen.

In an eighth group of preferred benzazepines of formula I, R¹² ishydrogen.

In a nineth group of preferred benzazepines of formula I, R¹¹ togetherwith R¹² is a bridge of the formula --O--CH₂ --CH₂ --, --O--CH═CH--,--CH₂ CH₂ --CH₂ -- or --CH₂ --CH═CH-- with the group comprising bothpossible orientations of the asymmetric bridges.

In a tenth group of preferred benzazepines of formula I, R¹³ is hydrogenor chloro.

The 2,3,4,5-tetrahydrobenzazepines of the general formula I can beprepared by one or more of the following methods A-D.

The starting materials for which the preparation is not describedherein, are either known compounds or compounds which may be prepared inanalogy with the preparation of known compounds or in analogy with knownmethods.

Method A

Compounds of the general formula III in which ##STR3## R³, R⁴, R¹⁰, R¹¹,R¹² and R¹³ are as defined for the compounds of the general formula Iand R^(7') is alkoxy and R^(8') is hydrogen or chloro or bromo can betransformed to benzazepines of formula IV by ring closure in an acidicmedium such as sulphuric acid, mixtures of trifluoroacetic acid andsulphuric acid (1-10%) or methanesulphonic acid at temperatures from-10° C. to 50° C. depending on the reaction medium. ##STR4##

This method is analogous to the method described in European patentapplication publication No. 200,455. All compounds of formula IV can beused as intermediates for the synthesis of benzazepines of formula I.

Method B

Compounds of the general formula IV in which R^(8') is halogen andR^(7') is hydroxy or alkoxy and the rest of the substituents are asdefined above can be dehalogenated in the 8-position by catalytichydrogenation e.g. palladium on carbon, as well at atmospheric pressureas at elevated pressure. Also, other halogens optionally present in thestarting material may at the same time, depending on the specificcompound and on the reaction conditions, be exchanged with hydrogen.

The solvents preferred are water at high pH (pH 9-13) ordimethylformamide or acetic acid and sodium acetate, however, othersolvents may also be used. The dehalogenated compounds have the generalformula V ##STR5## in which the substituents R³, R⁴ and R^(7') are asdefined above and the substituents R^(10"), R^(11"), R^(12") and R^(13")each are identical independently representing hydrogen, alkyl or alkoxy,except that where an optional further halogen in the starting materialhas been exchanged with hydrogen the corresponding double primedsubstituent in formula V designates hydrogen.

Method C

Compounds of the general formula V in which R^(7') is hydroxy or alkoxy,with the proviso when R³ is hydrogen the amine has to be protected byacylation, can be nitrated by generally known methods (see, for example,Jerry March: Advanced Organic Chemistry 3rd ed., McGraw-Hill, New York,1985) e.g. by treating a solution of a compound of the general formula Vin acetic acid or in a mixture of acetic acid and methylene chloridewith fuming nitric acid at temperatures from -10° C. to 10° C. Theproducts obtained will predominantly be mononitrated with the nitrogroup in the 8-position. In case R³ is hydrogen the protected amine canbe converted to a compound of formula V by deacylation per se.

The nitrated compounds can be used as such for therapeutic purposes oras intermediates for the synthesis of other benzazepines.

Method D

Compounds of the general formula IV or V in which the substituent R^(7')is alkoxy can be O-dealkylated by generally known methods to yield thecorresponding 7-hydroxy compounds, for example by treating a solution ofthe substrate in methylene chloride with boron tribromide at lowtemperature, e.g. -70° C. to 30° C., preferably -25° C. to 0° C. (see,for example, Theodora W. Greene: Protective Groups in Organic Synthesis,John Wiley, New York, 1981).

In some cases the succession of the reactions may be different from theone described here. For example the O-dealkylation may be carried outbefore the nitration.

The benzazepines of formula I are useful because of theirpharmacological activity. In particular, the compounds of formula I canbe useful as antipsychotics. The benzazepines of formula I areadministered in an effective amount to a host in need of treatment.

Compounds of formula I were tested for their binding to dopamine D1receptor in homogenates from rat striatum using the method described(Life Science vol. 37, p. 1971 (1985) P. Andersen et. al.) and theresults appear from table I, where the compounds of formula I tested arethe (+) enantiomere or racemic mixtures. K_(i) is the affinity of testedcompounds for the dopamine D1 receptor.

                  TABLE I                                                         ______________________________________                                                      K.sub.i nM                                                      Test Compound Dopamine D1 receptor                                            ______________________________________                                        Example 1     42                                                              Example 3     28                                                              Example 4     13                                                              Example 5     11                                                              Example 6     88                                                              Example 7     169                                                             ______________________________________                                    

As already mentioned, the benzazepines of the general formula given inTable II with X representing halogen have a low oral bioavailability.The increased bioavailability of the benzazepines according to thepresent invention compared to the corresponding benzazepines wherein Xis halogen can be demonstrated either by comparing the ratio between theED₅₀ by peroral and intraveneous administration in inhibitingamphetamine in rats or by comparing the absolute oral bioavailabilityfor the compounds in question as measured in mongrel dogs. Some testresults are stated in the following.

PHARMACOLOGICAL EXPERIMENTS

Following the method of Pedersen, V. and Christensen, A.V.: "Antagonismof methylphenidate-induced stereotyped gnawing in mice", Acta Pharmacol.et Toxicol. 31: 488-496, 1972, antagonism of dopamine-dependent,methyl-phenidate-induced gnawing behaviour of mice, was used to assessthe effects of the present D-1 antagonists. Further, the ratio of ED₅₀values obtained using i.v. administration and oral administration,respectively, was taken as an index of the bioavailability of the testdrugs. It was found that the presence of a nitrogroup in the 8thposition plays a crucial role for the p.o./i.v. effect ratio and, hence,for the bioavailability.

The following values were obtained:

                                      TABLE II                                    __________________________________________________________________________     ##STR6##                                                                                            ED.sub.50 -values                                                             (mg/kg)                                                                              Ratio                                                              K.sub.i                                                                           p.o.                                                                             i.v.                                                                              p.o./i.v.                                       __________________________________________________________________________    X = Cl                                                                               ##STR7##    0.14                                                                              6.5                                                                              0.017                                                                             382   (1)                                       X = NO.sub.2                                                                         ##STR8##    13  11.9                                                                             5.4 2.2   (2)                                       X = Cl                                                                               ##STR9##    0.2 4.5                                                                              0.06                                                                              75    (3)                                       X = NO.sub.2                                                                         ##STR10##   4.6 1.9                                                                              0.11                                                                              17.3  (4)                                       __________________________________________________________________________     (1) Reference substance SCH 23390                                             (2) Compound of example 4                                                     (3) Reference substance, compound g of example 5 in U.S. Pat. No.             4,751,222 (NOVO)                                                              (4) Compound of example 5                                                

Investigation of Absolute Bioavailability

The benzazepines are administered orally to dogs and subsequentlysamples of their blood plasma are analysed for the compound by aspecific HPLC-method. The area under the curve showing the oral plasmaconcentration versus time is calculated. This area is designated AUCi.v.

The absolute oral bioavailability, F, is calculated as the ratio betweenthe area representing the oral dose and the area for the intravenousdose according to the formula ##EQU1## The results are shown in TableIII.

                  TABLE III                                                       ______________________________________                                        Absolute bioavailability, F (%)                                               Substance                 F (%)                                               ______________________________________                                        8-chloro-7-hydroxy-3-methyl-5-(2,3-dihydro-                                                             5.5                                                 benzofuran-7-yl)-2,3,4,5-tetrahydro-1H-3-                                     benzazepine (note 1)                                                          (+)-7-hydroxy-3-methyl-8-nitro-5-(2,3-dihydro-                                                          65                                                  benzofuran-7-yl)-2,3,4,5-tetrahydro-1H-3-                                     benzazepine (note 2)                                                          ______________________________________                                         note 1:                                                                       reference substance, compound g of example 5 in U.S. Pat. No. 4,751,222       (NOVO)                                                                        note 2:                                                                       the compound according to example 5 of the present specification         

The acute toxicity of the compounds investigated is low.

The dosage of the compounds of the invention when employed in therapywill depend on the particular benzazepine of formula I in question onthe mode of administration and on the therapy desired. However, ingeneral, satisfactory results may be obtained with a daily dosage offrom 0,005 mg to about 5 mg per kg body weight, conveniently given individed doses 2 to 5 times a day or in sustained release form. Usually,dosage forms suitable for oral administration comprise from about 0.5 mgto about 250 mg of the benzazepine of formula I admixed with apharmaceutical carrier or diluent.

The benzazepines of formula I may be administered in the form of apharmaceutically acceptable acid addition salt. The invention alsorelates to pharmaceutical compositions comprising a benzazepine offormula I or a pharmaceutically acceptable salt thereof and, usually,such compositions also contain a pharmaceutical carrier or diluent. Thecompositions of this invention may be prepared by conventionaltechniques to be in conventional forms, for example, capsules ortablets.

The pharmaceutical carriers employed can be conventional solid or liquidcarriers. Examples of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate and stearicacid. Examples of liquid carriers are syrup peanut oil olive oil andwater. Similarly, the carrier or diluent may include any time delaymaterial well known to the art, such as glyceryl monostearate orglyceryl distearate alone or together with a wax.

If a solid carrier for oral administration is used, the preparation canbe tableted, placed in a hard gelatin capsule in powder or pellet formor in the form of a troche or lozenge. The amount of solid carrier willvary widely but will usually be frOm abOut 25 mg to about 1 g. If aliquid carrier is used, the preparation may, for example, be in the formof a syrup, an emulsion, a soft gelatin capsule, a sterile, injectablesolution or an aqueous or non-aqueous liquid suspension.

The pharmaceutical compositions of this invention may be made followingthe conventional techniques of the pharmaceutical chemist involvingmixing, granulating and compressing or variously mixing and dissolvingthe ingredients as appropriate to give the desired end product.

The route of administration may be any route which effectivelytransports the active compound to the desired place, such as oral orparenteral, the oral route being preferred.

The nomenclature used herein on the whole complies with the IUPACnomenclature, one of the main deviations being that in an attempt tofacilitate the reading of this specification, herein the position of thebenzazepine nucleus to which the phenyl group carrying the substituentsR¹⁰ -R¹³ is linked is always designated number 5. According to the IUPACnomenclature this position has the number 1 or 5, depending on thefurther substituents in the benzazepine nucleus. Further, in order tofacilitate the comparison of different series of substitution patternsthe substituents are not always arranged in alphabetical order in thenames of the compounds.

The features disclosed in the foregoing description and in the followingexamples and claims may, both separately and in any combination thereof,be material for realizing the invention in diverse forms thereof.

The invention is further illustrated by the following examples which,however, are not to be construed as limiting.

The starting material for which the preparation is not desribed hereinis described in European Patent Application publication No. 200,455(NOVO) and in European Patent Application publication No. 023 0270.

EXAMPLE 15-(2-fluorophenyl)-7-hydroxy-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine

(A)5-(2-fluorophenyl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine:

10.0 g8-chloro-5-(2-fluorophenyl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinewas dissolved in 500 ml acetic acid containing sodium acetate.Palladium-on-carbon was added and the suspension was heated to 60° C.Under vigorous stirring hydrogen was led through the suspension givingafter 48 h 7,9 g crystalline compound. Yield 72%.

NMR: >CH--OH 4,45 dd, C₆ H 5,95 d, C₈ H 6,45 d, C₇ OH 8,75 s ppm.respectively.

This compound was used for the next step without further purification.

(B)5-(2-fluorophenyl)-7-hydroxy-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-5-benzazepine:

5.0 g5-(2-fluorophenyl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinewas dissolved in 90 ml of a mixture of acetic acid and cooled inice-water bath 0° C. Under stirring was added 1,7 ml fuming nitric acidand the mixture was stirred in the cold for 1 h. The reaction mixturewas neutralized (pH 7.9) and the precipitate was extracted with ethylacetate, dried and evaporated. After column chromatography(kieselgel/CH₂ CH₂ : CH₃ OH 95: 5) was isolated yellow crystals. M.p.90°-94° C. (dec). NMR: C₅ H 4.61d C₆ H g 41% 6 s and C₉ H 7.88 s ppm.respectively.

EXAMPLE 27-hydroxy-3-methyl-8-nitro-5-(3-trifluoromethylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

(A)7-hydroxy-3-methyl-5-(3-trifluoromethylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinewas prepared in analogy with the method A in example 1. Yield 2,5 g,81%. NMR: C₅ H 4,25 dd: C₆ H 5,9d: C₈ H 6,5 dd; C₉ H 7,0 d ppm.respectively.

This compound was used for the next step without further purification.

(B)7-hydroxy-3-methyl-8-nitro-(3-trifluoromethylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepineis prepared in analogy with method B in example 1 giving 0.4 g (14%).M.p. 205°-210° C. (dec). NMR: C₅ H 5,08d: C₆ H 6,5 s: C₉ H 7.88s ppm.respectively.

EXAMPLE 3 7-hydroxy-3-methyl-8-nitro-5(2-methyl-phenyl)-2,3,45-tetrahydro-1H-3-benzazepine

(A) 1 g of7-methoxy-3-methyl-5-(2-methyl-phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinewas dissolved in a mixture of acetic acid (5 ml) and acetic anhydride (5ml). To this mixture was added fuming nitric acid and the reactionmixture was stirred at room temperature for 2 h. Crushed ice was addedto the reaction mixture and sodium hydroxide solution (6 N) was addedslowly to pH 7.5. This mixture was extracted with ethyl acetate, thecombined organic layer was dried and evaporated giving a solid which waspurified by column chromatography (kieselgel: CH₂ Cl₂ /CH₃ OH 98/2).Yield: 300 mg (27%). NMR: C₅ H 4.58d: C₆ H 6.11s: C₉ H 7.64s ppm.respectively.

This compound was used direct-y for the next step.

(B) 300 mg7-methoxy-3-methyl-8-nitro-5(2'-methyl-phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinewas dissolved in MeOH and cooled to -70° C. 1 g BBr₃ was added slowlyand the mixture was stirred for 1 h at -70° C., and stirring wascontinued for 1 h. Methanol was slowly added to distroy the excess ofBBr₃ and the mixture was evaporated to dryness. The raw material waspurified by column chromatography (kieselgel, CH₂ Cl₂ /CH₃ OH: 98/2)giving 110 mg of the desired compound. M.p. 59°-61° C. NMR: C₅ H 5.10d:C₆ H 6.20S: C₉ H 8.05s ppm. respectively.

EXAMPLE 4(R)-7-hydroxy-3-methyl-8-nitro-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine

(R)-7-hydroxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine wasprepared in analogy with the method described in example 1B giving 1.5 g(42%). M.p. 90°-92 ° C. NMR: C₅ H 4.37d: C₆ H 6.46s: C₉ H 7.88s ppm.respectively.

EXAMPLE 5

(+)-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine

(A)(+)-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

6.55 g, (0.020 mol)(+)-5-(benzofuran-7-yl)-8-chloro-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinewas dissolved in 1.0 N sodium hydroxide (100 ml, 0.100 mol) and water(100 ml). 10% palladium-on-carbon (3.0 g) was added, and the resultingsuspension was stirred under hydrogen at 20° C. and 100 kPa for 5 days.The reaction mixture was filtered and the filtercake was thoroughlywashed with 0.3 N hydrochloric acid (70 ml) and methanol (135 ml). ThepH of the combined filtrate and washings was brought to 8.0 and theresulting suspension was filtered. The filtercake was washed withwater/methanol (1/1) and dried in vacuo at 40° C. to give 3.45 g (76% ofthe theoretical yield) of the desired compound as white crystals.) M.p.227°-30° C.

(B) 3.0 g (3.03 mmol)(+)-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinewas dissolved in a mixture of methylene chloride (25 ml) and acetic acid(75 ml) at 10° C. and fuming nitric acid (0.5 ml) was added. Thereaction mixture was stirred for 2 h at 10°-15° C. Then the reactionmixture was evaporated to about 20 ml and diluted with water (100 ml).pH was adjusted to 8.5 and the water phase was extracted twice withmethylene chloride. The combined organic phases were dried andevaporated to give 2.1 g of crude product.

Purification by column chromatography (methylene chloride/methanol 9/1)gave 1.9 g of(+)-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepineas white crystals. M.p. 122°-3° C.

Calc.: 67.0% C, 5.9% H, 8.2% N.

Found: 66.8% C, 6.1% H, 8.1% N.

EXAMPLE 67-hydroxy-5-(5-indanyl)-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepin

(A) 7-hydroxy-5-(5-indanyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinewas prepared in analogy with example 1 A. Yield: 1.05 g (92%). M.p.213°-22° C. (dec). NMR: C₅ H 4.6d: C₆ H 5.65d: C₈ H 6.4dd: C₉ H 6.9dppm. respectively.

(B)7-hydroxy-5-(5-indanyl)-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepinewas prepared in analogy with example 1B. Yield: 0.45 g (39%). M.p.58°-63° C. NMR: C₅ H 4.66d: C₆ H 6.06s, C₉ H 7.8s ppm. respectively.

Calc.: 70.99% C, 6.55% H, 7.67% N.

Found: 70.43% C, 6.94% H, 7.77% N.

EXAMPLE 7trans-[6,7,7a,8,9,13b]-hexahydro-2-hydroxy-7-methyl-3-nitro-5H-benzo[d]naphto[2,1-b]azepine

trans-[6,7,7a,8,9,13b]-hexahydro-2-hydroxy-7-methyl-5H-benzo[d]naphto[2,1-b]azepine(642 mg) was dissolved in a mixture of 40 ml acetic acid and 4 ml ofwater, cooled to about 5° C. and treated with 0.5 ml of concentratednitric acid. After 1 h the reaction mixture was neutralized to pH 7.8.The precipitate was collected and purified by column chromatography(silicagel; THF+1% TEA) giving 95 mg (15% th). M.p. 115°-20° C. NMR: C₁H: 6.06 s: C₄ H 7.8s: C_(13b) H 4.75d ppm. respectively.

EXAMPLE 8 Preparation of Capsules

    ______________________________________                                        Ingredients          mg per capsule                                           ______________________________________                                        (+)-7-hydroxy-3-methyl-8-nitro-5-                                                                  125                                                      (2,3-dihydrobenzofuran-7-yl)-                                                 2,3,4,5-tetrahydro-1H-3-benzazepine                                           hydrobromide                                                                  magnesium stearate    2                                                       lactose              200                                                      ______________________________________                                    

The above ingredients were thoroughly mixed and placed into hard gelatincapsules. Such capsules were administered orally to subjects in need oftreatment one or more times daily.

EXAMPLE 9 Preparation of Tablets

    ______________________________________                                        Ingredients          mg per tablet                                            ______________________________________                                        (+)-7-hydroxy-3-methyl-8-nitro-5-                                                                  200                                                      (2,3-dihydrobenzofuran-7-yl)-                                                 2,3,4,5-tetrahydro-1H-3-benzazepine                                           hydrobromide                                                                  corn starch          46                                                       polyvinyl pyrrolidone                                                                              12                                                       magnesium stearate    1                                                       ______________________________________                                    

The benzazepine was thoroughly mixed with two thirds of the corn starchand granulated. The granules obtained were dried, mixed with theremaining ingredients and compressed into tablets.

We claim:
 1. A 2,3,4,5-tetrahydro-1H-3-benzazepine selected from those of the formula I ##STR11## wherein R³ represents C₁₋₃ -alkyl or C₃₋₇ -cycloalkyl; R⁴ represents hydrogen; R⁷ represents hydroxy or lower alkoxy; one of R¹⁰, R¹¹, R¹² and R¹³ represents trifluromethyl and the others independently represent hydrogen or R¹¹ together with either R¹⁰ or R¹² represents a bridge chosen from among --O--CH₂ --CH--, --O--CH₂ --CH₂ --CH₂ --, --O--CH═CH--, --CH₂ --CH₂ --CH₂ --, --CH₂ --CH═CH-- and --CH₂ --CH₂ --CH₂ --CH₂ --, and the remainder of R¹⁰, R¹¹, R¹² and R¹³ each represents hydrogen, and pharmaceutically-acceptable acid additional salts thereof.
 2. Benzazepine according to claim 1 wherein R⁷ is hydroxy.
 3. Benzazepine according to claim 2 wherein R⁴ is hydrogen and R¹⁰ and R¹¹ represent a bridge, said bridge being --O--CH₂ --CH₂ -- or --O--CH═CH-- or --CH₂ --CH═CH-- or --CH₂ --CH₂ --CH₂ --.
 4. Benzazepine according to claim 3 wherein R¹² and R¹³ represent hydrogen.
 5. Benzazepine according to claim 2 wherein R¹² and R¹³ represent hydrogen.
 6. Benzazepine according to claim 1 wherein R⁴ is hydrogen and R¹⁰ and R¹¹ represent a bridge, said bridge being --O--CH₂ --CH₂ -- or --O--CH═CH-- or --CH₂ --CH═CH-- or --CH₂ --CH₂ --CH₂ --.
 7. Benzazepine according to claim 6 wherein R¹² and R¹³ represent hydrogen.
 8. Benzazepine according to claim 1 wherein R¹² and R¹³ represent hydrogen.
 9. A compound according to claim 1 which is (+)-7-hydroxy-3-methyl-8-nitro-5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine.
 10. A compound according to claim 1 which is 7-hydroxy-3-methyl-8-nitro-5-(3-trifluoromethylphenyl)-2,3,4,5 -tetrahydro-1H-3-benzazepine.
 11. A compound according to claim 1 wherein the substituent in the 5 position of the benzazepine nucleus is 2,3-dihydrobenzofuranyl-7-yl.
 12. A compound according to claim 1 wherein the substituent in the 5 position of the benzazepine nucleus is 5-indanyl.
 13. A compound according to claim 1 which is 7-hydroxy-5-(5-indanyl)-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine.
 14. A pharmaceutical composition useful for treating CNS ailments containing an effective amount of a benzazepine of claim 1 or a pharmaceutically-acceptable acid addition salt thereof together with a pharmaceutically-acceptable carrier or diluent.
 15. A pharmaceutical composition according to claim 14, which contains between 0.1 mg and 250 mg of the active ingredient or a pharmaceutically acceptable acid addition salt thereof per dose unit.
 16. A method of treating a central nervous system ailment sensitive to the dopamine D1 receptor comprising the step of administering to the said subject an effective amount of a compound having the formula I: ##STR12## wherein R³ represents C₁₋₃ -alkyl or C₃₋₇ -cycloalkyl; R⁴ represents hydrogen;R⁷ represents hydroxy or lower alkoxy; R¹⁰, R¹¹, R¹² independently represent hydrogen, halogen, or trifluoromethyl, alkyl, or alkoxy; or R¹⁰ together with R¹¹ represents a bridge or R¹¹ together with R¹² represents a bridge, the bridge in both cases being chosen from among --O--CH₂ --CH--, --O--CH₂ --CH₂ --CH₂ --, --O--CH═CH--, --CH₂ CH₂ --CH₂ --, --CH₂ --CH═CH-- or --CH₂ --CH₂ --CH₂ --CH₂ --; and wherein R¹³ represents hydrogen, halogen, or lower alkyl,or a pharmaceutically-acceptable acid-addition salt thereof.
 17. A method according to claim 16 wherein the ailment is schizophrenia or manic-depressive disorders.
 18. A method according to claim 16 wherein the substituent in the 5 position of the benzazepine nucleus is 2,3-dihydrobenzofuranyl-7-yl.
 19. Method according to claim 16 wherein R⁷ is hydroxy.
 20. Method according to claim 19 wherein R⁴ is hydrogen and R¹⁰ and R¹¹ represent a bridge, said bridge being --O--CH₂ --CH₂ -- or --O--CH═CH-- or --CH₂ --CH═CH-- or --CH₂ --CH₂ --CH₂ --.
 21. Method according to claim 19 wherein R¹² and R¹³ represent hydrogen.
 22. Method according to claim 16 wherein R⁴ is hydrogen and R¹⁰ and R¹¹ represent a bridge, said bridge being --O--CH₂ --CH₂ -- or --O--CH═CH-- or --CH₂ --CH═CH-- or --CH₂ --CH₂ --CH₂ --.
 23. Method according to claim 22 wherein R¹² and R¹³ represent hydrogen.
 24. Method according to claim 16 wherein R¹² and R¹³ represent hydrogen.
 25. Method according to claim 16 wherein the compound is (+)-7-hydroxy-3-methyl-8-nitro-5-(2,3-dihydrobenzofuran-7-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine.
 26. Method of claim 16 wherein the compound is 5-(2-fluorophenyl-7-hydroxy-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine.
 27. Method of claim 16 wherein the compound is 7-hydroxy-3-methyl-8-nitro-5-(3-trifluoromethylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine.
 28. Method of claim 16 wherein the compound is 7-hydroxy-3-methyl-8-nitro-5-(2-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine.
 29. Method of claim 16 wherein the compound is (R)-7-hydroxy-3-methyl-8-nitro-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
 30. Method of claim 16 wherein the compound is 7-hydroxy-5-(5-indanyl)-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine. 